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van der Harst, P.* ; van Setten, J.* ; Verweij, N.* ; Vogler, G.* ; Franke, L.* ; Maurano, M.T.* ; Wang, X.* ; Mateo Leach, I.* ; Eijgelsheim, M.* ; Sotoodehnia, N.* ; Hayward, C.* ; Sorice, R.* ; Meirelles, O.* ; Lyytikäinen, L.-P.* ; Polasek, O.* ; Tanaka, T.* ; Arking, D.E.* ; Ulivi, S.* ; Trompet, S.* ; Müller-Nurasyid, M. ; Smith, A.V.* ; Dörr, M.* ; Kerr, K.F.* ; Magnani, J.W.* ; Del Greco M, F.* ; Zhang, W.* ; Nolte, I.M.* ; Silva, C.T.* ; Padmanabhan, S.* ; Tragante, V.* ; Esko, T.* ; Abecasis, G.R.* ; Adriaens, M.E.* ; Andersen, K.* ; Barnett, P.* ; Bis, J.C.* ; Bodmer, R.* ; Buckley, B.M.* ; Campbell, H.* ; Cannon, M.V.* ; Chakravarti, A.* ; Chen, L.Y.* ; Delitala, A.* ; Devereux, R.B.* ; Doevendans, P.A.* ; Dominiczak, A.F.* ; Ferrucci, L.* ; Ford, I.* ; Gieger, C. ; Harris, T.B.* ; Haugen, E.* ; Heinig, M. ; Hernandez, D.G.* ; Hillege, H.L.* ; Hirschhorn, J.N.* ; Hofman, A.* ; Hubner, N.* ; Hwang, S.J.* ; Iorio, A.* ; Kähönen, M.* ; Kellis, M.* ; Kolcic, I.* ; Kooner, I.K.* ; Kooner, J.S.* ; Kors, J.A.* ; Lakatta, E.G.* ; Lage, K.* ; Launer, L.J.* ; Levy, D.* ; Lundby, A.* ; Macfarlane, P.W.* ; May, D.* ; Meitinger, T. ; Metspalu, A.* ; Nappo, S.* ; Naitza, S.* ; Neph, S.* ; Nord, A.S.* ; Nutile, T.* ; Okin, P.M.* ; Olsen, J.V.* ; Oostra, B.A.* ; Penninger, J.M.* ; Pennacchio, L.A.* ; Pers, T.H.* ; Perz, S. ; Peters, A. ; Pinto, Y.M.* ; Pfeufer, A. ; Pilia, M.G.* ; Pramstaller, P.P.* ; Prins, B.P.* ; Raitakari, O.T.* ; Raychaudhuri, S.* ; Rice, K.M.* ; Rossin, E.J.* ; Rotter, J.I.* ; Schafer, S.* ; Schlessinger, D.* ; Schmidt, C.O.* ; Sehmi, J.* ; Sillje, H.H.W.* ; Sinagra, G.* ; Sinner, M.F.* ; Slowikowski, K.* ; Soliman, E.Z.* ; Spector, T.D.* ; Spiering, W.* ; Stamatoyannopoulos, J.A.* ; Stolk, R.P.* ; Strauch, K. ; Tan, S.T.* ; Tarasov, K.V.* ; Trinh, B.* ; Uitterlinden, A.G.* ; van den Boogaard, M.J.* ; van Duijn, C.M.* ; van Gilst, W.H.* ; Viikari, J.S.* ; Visscher, P.M.* ; Vitart, V.* ; Völker, U.* ; Waldenberger, M. ; Weichenberger, C.X.* ; Westra, H.J.* ; Wijmenga, C.* ; Wolffenbuttel, B.H.* ; Yang, J.* ; Bezzina, C.R.* ; Munroe, P.B.* ; Snieder, H.* ; Wright, A.F.* ; Rudan, I.* ; Boyer, L.A.* ; Asselbergs, F.W.* ; van Veldhuisen, D.J.* ; Stricker, B.H.* ; Psaty, B.M.* ; Ciullo, M.* ; Sanna, S.* ; Lehtimäki, T.* ; Wilson, J.F.* ; Bandinelli, S.* ; Alonso, A.* ; Gasparini, P.* ; Jukema, J.W.* ; Kääb, S.* ; Gudnason, V.* ; Felix, S.B.* ; Heckbert, S.R.* ; de Boer, R.A.* ; Newton-Cheh, C.* ; Hicks, A.A.* ; Chambers, J.C.* ; Jamshidi, Y.* ; Visel, A.* ; Christoffels, V.M.* ; Isaacs, A.* ; Samani, N.J.* ; de Bakker, P.I.*

52 Genetic loci influencing myocardial mass.

J. Am. Coll. Cardiol. 68, 1435-1448 (2016)
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BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Qrs ; Electrocardiogram ; Genetic Association Study ; Heart Failure ; Left Ventricular Hypertrophy; Left-ventricular Hypertrophy; Cardiac-hypertrophy; Regulatory Dna; Electrocardiogram; Mortality; Disease; Voltage; Dysfunction; Genome; Heart
Language
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 0735-1097
e-ISSN 1558-3597
Journal Journal of the American College of Cardiology
Quellenangaben Volume: 68, Issue: 13, Pages: 1435-1448 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
Institute of Computational Biology (ICB)
Institute of Human Genetics (IHG)
Institute of Biological and Medical Imaging (IBMI)
Institute of Bioinformatics and Systems Biology (IBIS)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
30205 - Bioengineering and Digital Health
30505 - New Technologies for Biomedical Discoveries
Research field(s) Genetics and Epidemiology
Enabling and Novel Technologies
PSP Element(s) G-504100-001
G-504091-001
G-504091-004
G-553500-001
G-500700-001
G-505500-003
G-503700-001
G-504000-001
DOI 10.1016/j.jacc.2016.07.729
WOS ID WOS:000385933800009
Scopus ID 84990929556
PubMed ID 27659466
Erfassungsdatum 2016-10-04
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